Dipropyl-barbituric acid, analogous derivatives, and process of making them.



UNITED STATES Patented February 14, 1905.

PATENT OFFICE.

EMIL FISCHER, OF BERLIN, GERMANY, ASSIGNOR TO THE FIRM OF E. MERCK, OFDARMSTADT, GERMANY, A (JOPARTNERSHIP.

DlPROPYL-BARBITURIC ACID, ANALOGOUS DERIVATIVES, AND PROCESS OF MAKINGTHEM.

SPECIFICATION forming part of Letters Patent No. 782,740, dated February14, 1905.

Original application filed January 22, 1903, Serial No. 140,108. Dividedand this application filed August 16, 1904. Serial No. 220,967.

(Specimens) 1 To all whom it may concern:

Be it known that I, EMIL FIsoIIER, a subject of the Emperor of Germany,and a resident of Berlin, Germany, have invented new and usefulImprovements in Dipropyl Barbituric Acid and Analogous Derivatives andProcess of Making Them; and hereby I declare the following to be a clearand exact description of my invention.

My invention relates to the production of disubstituted derivatives ofbarbituric acid.

The present application, which is a divisional application from myapplication, Serial No. 140,108, filed January 22, 1903, coversspecifically the new barbituric-acid derivatives, containing assubstituting groups two radicals, such as propyl, for which may besubstituted any higher homologous and analogous group and which weredenoted in example Nos. 3, 5, 7, 11 of said application. These newproducts are characterized by the general formula in which 00 meanssubstituting groups of the above description. According to my researchesthese new compounds are' obtained by condensing disubstitutedmalonic-acid-ester derivatives, containing as substituting groups thepropyl radical for which may be substituted-any higher homologous andanalogous groups, with urea in the presence of metal alcoholate. In thismanner disubstituted barbituric acids are obtained which form colorlesscrystals diflicultly soluble in water, soluble in sodium hydrate andpotassium hydrate, thus forming salts by the replacement of the hydrogenof the NH group by metal. These products possess therapeutic value ashypnotics, the average dose for medicinal purposes being one-half to onegram.

In carrying out my process practically I can proceed as follows:

1. Dz'propyl bandit uric acid. Twenty parts, by weight, ofdipropyl-malonic-acid die-thyl ester are introduced into a cold solutionof 5.7 parts, by weight, of sodium in one hundred and ten parts, byweight, of absolute alcohol. Then 7. 5 parts, by weight,of urea areadded, and the mixture is heated to about 100 centigrade in a closedvessel for four hours. The hereby-formed sodium salt ofdipropylbarbituric acid is soluble in alcohol, and the slightprecipitate occurring during the operation consists almost altogether ofsodium carbonate. Therefore to isolate the dipropylbarbituric acid thealkaline alcoholic solution is diluted with water supersaturated withhydrochloric acid .and its alcohol removed by evaporation.Dipropylbarbituric acid being poorly soluble in water, separates firstas a tenacious oil, but on cooling soon solidifies. On filtration it ispurified by recrystallizing from hot water. It then forms short thickcolorless crystals. The yield is also in this case a pretty good one.The acid has the composition It melts at 145 centigrade and isdiilicultly solter with the urea in the presence of sodium ethylate maybe brought about exactly as in the above example, onlyit is advisable toprolong the duration of the heat to six to seven hours.Di-iso-butyl-barbituric acid dissolves readily in hot alcohol, withgreat difficulty in hot water, and crystallizes from the latter oncooling in colorless thin leaflets. The acid has the compositionCmIIzoOsNa and melts at 173.5 centigrade.

3. I)iso-amy l-bmMtm'ic (wicZ.This compound is prepared in the same wayas the compound described above from di-iso-amylmalonic diethyl esterand is soluble in water with still greater difiiculty than the other. Itcrystallizes from hot water in line colorless little needles. Themelting-point of this acid is 172 centigrade.

4. Dt'beneg Z-bcMMZM'iC acicZ.-4E.7 parts of sodium are dissolved inseventy-five parts of alcohol. Twenty parts of dibenzyl-malonicdiethylester and 4.8 parts of urea are added, and a temperature ot'lOE) to 108centigrade is applied for four hours. The solution filtered from theprecipitated carbonate is diluted with water, and the alcohol isevaporated under reduced pressure. Hereby a mass (insoluble in alkali)is precipitated and after the addition of some alkali and digestion withthe liquid is filtered 0d. The mother-lye on being acidulatedprecipitates dibenzyl-barbituric acid, which is purified byrecrystallizing from hot alcohol. The melting-point of this acid is 222centigrade.

Although I have above described examples by which the disubstitutedbarbituric acids may be obtained, nevertheless I do not wish to beunderstood as thereby excluding equivalentsfor the ingredients, theapparatus, or the operations employed in the process. It is probablethat substitutes may be employed with out departing from the scope ofthe invention intended to be secured hereby. For example, aeetyl ureamay be employed in the described processes without changing theresulting products, the acetyl group being split off in the reaction.

The new disubstituted barbituric acids possess the property of formingsalts with many metals for example, the alkali metals-the hydrogen ofthe NH group being replaced by the metal.

Having now described my invention and in what manner the same is to beperformed,what

I claim as new, and desire to secure by Letters Patent. is

1. The herein-described new process of making disubstituted barbituricacids having the general formula:

in which 00 represents the propyl radical for which may be substitutedany higher homologous and analogous groups, consistingin condensing thecorresponding disubstituted malonie-acid esters with urea in thepresence of metal alcoholate,decomposing the thus-formed sodium salts ofthe disubstituted barbituric acids by means of acid, producing therebythe free disubstituted 'barbituric acids.

2. The herein-described new process of making dipropyl barbituric acid,consisting in condensing dipropyl malonic ester with urea in thepresence of metal alcoholate and transforming the thus-formed sodiumsalts of the dipropyl barbituric acid into the free dipropyl barbituricacid by means of acid.

3. The herein-described new products,being disubstituted barbituricacids, having the general formula:

in which or represents the propyl radical, for which may be substitutedany higher homologous and analogous groups, and characterized by formingcrystals diificultly soluble in hot water and soluble in solutions ofalkali and in the salt form of which the hydrogen of the NH group isreplaced by the alkali metal.

4. The herein-described new dipropyl barbituric acid, which in the acidform melts at 14:5 centigrade when recrystallized from hot water and issoluble in solutions of sodium hydrate and potassium hydrate and in thesalt form of which themetal replaces the hydrogen of the NH group.

in testimony whereof I have signed my name in the presence of twosubscribing witnesses.

EMIL FISCHER.

\Vi tn esses:

E. ALDERHALDEN, F. REUTER.

